Despite aggressive public education campaigns, maternal tobacco smoking remains an important public health problem. Our murine model of gestational maternal smoking demonstrates significant alveolarization abnormalities, including fewer alveoli and decreased elastin expression. These findings are associated with several abnormalities in the retinoic acid (RA) pathway which would decrease RA signaling, including 1) decreased mRNA and protein expression for retinoic acid receptor-alpha;2) decreased expression of retinaldehyde dehydrogenase-2;3) decreased RA signaling activation;and 4) decreased expression of genes regulated by RA, such as smooth muscle actin. Intact RA signaling is required for normal development of pulmonary epithelium, vasculature, and elastin expression. We hypothesize that maternal smoking disrupts retinoic acid signaling, thereby causing injury in the immature lung and lessening baseline pulmonary reserve, which increases the susceptibility of the postnatal lung to subsequent environmental insults. We will test this hypothesis by investigating two specific aims: Specific Aim 1: To test the hypothesis that decreased retinoic acid pathway signaling during critical stages of lung development and maturation is a significant and reversible mechanism of lung damage caused by maternal smoking. We will use our murine model of developmental smoke exposure to test this hypothesis by treating pups with all-trans retinoic acid during the saccular and early alveolar stage of lung development. Specific Aim 2: To test the hypothesis that developmental exposure to second-hand tobacco smoke increases the lung damage caused by postnatal pulmonary insults. We will use our murine model of developmental exposure to second-hand tobacco smoke followed by the murine model of tobacco-induced emphysema to investigate whether mice exposed to second-hand tobacco during development are more vulnerable to the effects of direct postnatal smoking. Completion of these aims will accomplish several goals and serve as a critical bridge to future studies. First, amelioration of the pulmonary effects of maternal smoking by RA supplementation will establish that this pathway is a critical mediator of the effects of maternal smoking in the immature lung, thereby providing the rationale for both future mechanistic studies and possible novel clinical interventions to improve pediatric lung health in children exposed to maternal smoking. Second, establishing whether developmental tobacco smoke exposure increases postnatal vulnerability to tobacco exposure will provide insights into the contributions of abnormal development to adult lung disease. Thus, these two focused investigations will provide the theoretic underpinning for future bench studies examining the pathophysiologic effects of maternal smoking and will indicate possible novel preventative strategies for adult lung disease. Project Narrative: Maternal smoking remains an important clinical problem despite aggressive anti-smoking educational programs. These studies will use an animal model to address two important questions about the pulmonary effects of maternal smoking: 1) determining whether exposure to maternal smoking during lung development increases the vulnerability of the lung to postnatal injury and 2) determining whether supplementing retinoic acid signaling can be an effective strategy to decrease the effects of maternal smoking. Addressing these questions will provide insight into the role early developmental events have in causing adult lung disease and will suggest novel therapeutic interventions to protect the lung from the effects of maternal smoking.